Cancer alters the circadian clock to survive

Tumor cells use the unfolded protein response to alter circadian rhythm, which contributes to more tumor growth, Hollings Cancer Center researchers at the Medical University of South Carolina (MUSC) find. A key part of the circadian clock opposes this process. For tumors to grow and spread, cancer cells must make larger than normal amounts of nucleic acids and protein, so they can replicate themselves. Yet in both normal and cancer cells that increase their synthesis of protein, a small percent of those proteins do not fold properly.

When that happens, the cell activates its unfolded protein response (UPR), which slows down the making of new proteins while the misfolded proteins are refolded. Eventually, the buildup of misfolded proteins becomes toxic and leads to cell death. However, cancer cells have learned to use the UPR to slow protein synthesis when needed, in order to handle the backlog of misfolded proteins. This helps them survive in conditions that would kill normal cells.

This pattern of adaptation is often seen in tumor cells. UPR and circadian rhythm are linked together to lead the clockwork of the cell and also that cancer cells use the UPR to manipulate the circadian clock in ways that allow them to survive conditions that are toxic to normal cells. Researchers formulated a new idea based on what was known about protein synthesis in the cell. The UPR is altered in tumors, and second, cells establish a circadian rhythm to regulate metabolism by producing levels of certain proteins that rise and fall in coordination with natural cycles of light and dark.

 Scientists had observed that circadian rhythm is altered in tumor cells. Since protein production is tied to circadian rhythm. Research team used chemicals to activate the UPR in osteosarcoma cells. They found that, when activated, the UPR changes levels of an important protein called Bmal1, which is a transcription factor that rises and falls with cycles of light and dark. As it does, it regulates the expression of major circadian rhythm genes.

When cells were exposed to cycles of light and dark, Bmal1 levels peaked during dark hours. But when the UPR was chemically activated, Bmal1 stayed low during both light and dark phases, which caused a phase shift in the expression of circadian genes. When one of the main parts of the UPR machinery was absent in cells, the phase shift did not happen.

Levels of the circadian protein Bmal1 continued to decrease, as the UPR was increasingly activated. In rodents that had their light-dark cycles suddenly reversed, Bmal1 stopped rising and falling - a clear sign that their circadian rhythms were disrupted. Shifts in light exposure activated the UPR in those rodents' cells.

 The team found that patients with breast, gastric or lung cancers survived longer when they had higher levels of Bmal1 protein. In myc-driven cancers, the UPR was causing the loss of Bmal1 protein, which caused the tumors to grow. Myc-driven tumors lost circadian rhythm, whereas normal cells maintained it. Conversely, high levels of Bmal1 overtook the UPR, thereby allowing protein synthesis to continue, which was toxic to tumor cells . In this way, Bmal1 directly encourages protein synthesis.

Human cancer suppresses circadian rhythm by controlling protein synthesis through Bmal1. Cancer cells survived longer by using the UPR to suppress Bmal1 and short-circuit their circadian rhythms. These results are important for human biology. Every single normal cell in human body has circadian oscillation, resetting the circadian rhythms in cancer cells slows down their proliferation.
          haleplushearty.blogspot.com

The use of metabolism to subtype hepatoblastoma tumors

Hepatoblastoma is a rare pediatric liver cancer, usually diagnosed in the first three years of life. There are many subtypes of hepatoblastoma, the two major ones are fetal and embryonal.
Scientists have identified new biomarkers that could accurately classify the two main subtypes of hepatoblastoma, a children liver cancer.

Different types of hepatoblastoma use different nutrients to grow. Some use glucose or fatty acids. The genetics of hepatoblastoma involves frequent mutations in the gene CTNNB1. This gene produces the protein beta-catenin, which is involved in cell-cell adhesion and gene transcription. Because of its dual function, mutations of the CTNNB1 gene can cause hepatoblastoma cancer.

Beta-catenin is a component of a signaling pathway known as Wnt/beta-catenin, which is responsible for regulating the expression of multiple genes. Many components of the Wnt/beta-catenin pathway are affected and overactive in various tumors.

Researchers examined the relationship between the CTNNB1 gene and the cell's metabolism, they discovered that beta-catenin, as part of the Wnt signaling pathway directly regulates the expression of a gene that produces a glucose transporter protein. GLUT3

They used RNA sequencing to identify molecular and metabolic features that are specific to hepatoblastoma. This approach revealed that several enzymes involved in the metabolism of glucose are overexpressed in embryonal hepatoblastoma cells as compared to fetal hepatoblastoma cells.

Embryonal hepatoblastoma cells show high levels of glucose uptake, they also discovered that these cells are very sensitive to the perturbation of an enzyme involved in the cell's use of glucose. They immunohistochemistry of the three metabolic biomarkers to distinguish embryonal from fetal components out of a large panel of human hepatoblastoma biopsies.

The study shows that the Wnt/beta-catenin pathway is important for reprograming the energy management of tumor cells. It also provides a new
metabolic classification of human hepatoblastoma that can help oncologists develop novel diagnostic methods and treatments.
          haleplushearty.blogspot.com

Exercise prevents breast cancer

Intense physical activity that cause breathlessness creates a chemical release in the body. This releases compounds called catecholamines and epinephrine suppress the growth of tumour cells.

 Exercise training and epinephrine did not completely prevent tumor formation, but induced reduction.
Exercise training can not replace anti-cancer therapy, but could be an effective supportive strategy and improves cancer treatment.

Researchers used experimental mice implanted with human breast cancer tumors as well as tumor cells in test tubes to investigate how serum samples from healthy women and breast cancer patients before and after exercise affect the development of the breast tumor cells, and the mechanism involved.

They discovered that serum samples taken after exercise reduced the ability of tumor cells to grow in test tubes or in mice. Less than half of mice with tumors steeped in post-exercise serum developed tumors, compared with 90 percent of mice with tumors not exposed to post-exercise serum.

The researchers traced the anti-tumor activity to a rise in epinephrine and norepinephrine that occurs with moderately intense exercise. Studies have shown that regular fitness can reduce risk of breast cancer and reoccurrence in those who already have it.
          haleplushearty.blogspot.com

Zika kills brain cancer stem cells

Zika virus is a mosquito-borne infection known for causing birth defects in unborn fetuses. Latest research discovered that it is possible to use the virus to target tumor cells in adult brains. Combining Zika virus with chemotherapy and radiation can be use to remove brain tumors.

Glioblastoma is the most common and deadly forms of brain cancer with patients dying within two years of diagnosis. The growth and development of glioblastomas is driven by stem cells that proliferate and give rise to other tumor cells.

Stem cells of the cancer are hard to kill because they avoid body's immune system and are resistant to chemotherapy and radiation. Killing these cells is very important to prevent new tumors from recurring after the original tumor has been surgically removed.

 Glioblastoma can occur in any part of the brain, when glioblastoma is diagnosed, microfibers can spread to the rest of the brain which magnetic resonance imaging MRI would not detect. It is common in men between the age of 50 and 60, and there is no link between developing glioblastoma and having a previous cancer history.

Intense exposure to radiation increases the risk of brain cancer. Zika virus disrupts fetal brain development targeting neural stem and progenitor cells, however the virus' effects on adult brains are less severe.

 The preference of Zika virus for neural precursor cells could be leveraged against glioblastoma stem cells, researchers found the virus infected and killed patient-derived glioblastoma stem cells compared with other glioblastoma cell types or normal neural cells.

When mice with aggressive glioblastoma were injected with a mouse-adapted strain of Zika virus, the virus slowed tumor growth and significantly extended the animals' lifespan.

Researchers also tested a mutated strain of Zika on body's immune response, which was more effective when combined with a chemotherapy drug, temozolomide, that usually has little effect on these cells. Zika virus can kill the kind of glioblastoma cells that tend to be resistant to current treatments.
         haleplushearty.blogspot.com

Killer peptide for killing cancer cells

Death of therapy sensitive cancer cells leads to the release of a killer peptide that can eliminate therapy resistant cells. Tumor relapse is a problem after cancer treatment, because primary tumor cells always contain therapy resistance cancer cells that continue to proliferate after the therapy-sensitive cells have been removed.

A Par-4 amino-terminal fragment PAF that is released by diverse therapy-sensitive cancer cells after therapy-induced cleavage of the tumor suppressor Par-4 protein. PAF caused death in cancer cells resistant to therapy and prevented metastatic tumor growth.

Naturally generated PAF could potentially be harnessed to target cancer cells to overcome metastasis and therapy resistance in tumors. The PAF entered only cancer cells, not normal cells, keeping healthy tissue alive.

The use of sensitive cells in the tumor to release this peptide to destroy the resistant cells will be a good method in killing cancer cells. PAF development is a good method against therapy resistant tumor metastasis because there is no other treatment option for it.
           haleplushearty.blogspot.com